The overall goal of the studies presented in this proposal is to identify the immunological mechanisms that mediate effective protection from shigellosis following vaccination and natural infection with Shigella. Shigella is a global infection that disseminates rapidly in settings where there is crowding and inadequate sanitation. Given the shortcomings of available public health measures to successfully control this infection, the appearance of drug resistance and concerns about its potential use in bioterrorism, the development of safe and effective vaccines to S. dysenteriae 1, S. flexneri 2a and S. sonnei is urgently needed. However, Shigella vaccine development has been hampered by a considerable lack of information of the specific determinants of protective immunity. Thus, the understanding of the immunological correlates of protection in humans to Shigella spp. is of great importance. Our working hypothesis is that both cell-mediated immunity and antibody responses play a central role in protection of volunteers from shigellosis following immunization with attenuated Shigella vaccine candidates or infection with wild-type Shigella. Specifically, using serum, stool and peripheral blood mononuclear cell specimens obtained from volunteers immunized with attenuated strains of S. dysenteriae, S. sonnei or S. flexneri 2a or challenged with wild-type S. dysenteriae (zlstxA strain), S. sonnei or S. flexneri 2a, we propose to test the following hypotheses: (1) secretion of interferon-gamma, and other cytokines to key Shigella proteins involved in cell invasion (e.g., IpaB, IpaC and IpaD) following immunization or challenge of volunteers with Shigella is mediated by CD4 + T cells and restricted by class II major histocompatibility complex molecules; (2) immunization or challenge of volunteers with Shigella elicits the appearance in circulation of specific cytotoxic T lymphocytes; (3) protective CMI against Shigella depends on a defined set of immunodominant epitopes derived from Shigella antigens; (4) immunization or challenge of volunteers with Shigella elicits the appearance in serum and stools of antibodies directed not only to LPS, but also to key molecules involved in Shigella invasion, e.g., IpaB, IpaC, IpaD and other Shigella proteins and (5) immunization or challenge of volunteers with Shigella elicits the appearance in circulation of (a) specific T and B lymphocytes expressing gut homing molecules (e.g., integrin alpha4beta7)and (b) expanded effector (Teff) and peripheral memory T cell (TEM)pools.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057927-03
Application #
7066091
Study Section
Special Emphasis Panel (ZRG1-VACC (02))
Program Officer
Van de Verg, Lillian L
Project Start
2004-05-01
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
3
Fiscal Year
2006
Total Cost
$513,809
Indirect Cost
Name
University of Maryland Baltimore
Department
Pediatrics
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Kotloff, Karen L; Simon, Jakub K; Pasetti, Marcela F et al. (2007) Safety and immunogenicity of CVD 1208S, a live, oral DeltaguaBA Deltasen Deltaset Shigella flexneri 2a vaccine grown on animal-free media. Hum Vaccin 3:268-75
Levine, Myron M; Kotloff, Karen L; Barry, Eileen M et al. (2007) Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road. Nat Rev Microbiol 5:540-53
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